Alendronate sodium, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium, having the formula ##STR2##
is an agent for combating bone resorption in bone diseases including osteoporosis and Paget's disease.
Various methods for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, or alendronic acid, are known in the art and have been disclosed in M. I. Kabachnik et al., Synthesis and Acid-Base and Complexing Properties of Amino-Substituted alpha-hydroxylakylidene-diphosphonic Acids, Izu. Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S. Pat. Nos. 4,407,761, 4,621,077, 4,705,651, 5,039,819 and 5,159,108.
A well known process for preparing alendronic acid is as follows (see also e.g. GB 2118042): ##STR3##
It has been reported that a solidification problem occurs when this process is performed on a large scale. The abbreviation GABA is defined hereinafter as 4(gamma)-aminobutyric acid.
U.S. Pat. No. 4,922,007 describes the preparation of alendronate sodium in trihydrate form, wherein 4-aminobutyric acid is reacted with phosphorous acid and phosphorous trichloride in the presence of methanesulfonic acid followed by the addition of sodium hydroxide. However, it has been reported that methanesulfonic acid reacts with the phosphorus trichloride and under adiabatic conditions the reaction becomes self-heating at 85.degree. C., and an uncontrolled exotherm occurs at &gt;140.degree. C.
WO 98/34940 describes a process for preparing alendronic acid, which comprises reacting 4-aminobutyric acid with phosphorous acid and phosphorous trichloride in the presence of polyalkylene(glycol). However, it was reported that large quantities of polyalkylene(glycol) as well as toluene participate in this reaction, which renders it inefficient on a large scale.
Thus, there remains a need for a homogeneous, safe and efficient process for preparing alendronic acid.